Quadrupoles are ion confinement devices that are utilized to perform several important functions within mass spectrometer systems. For example, such devices are frequently employed as simple ion guides, as mass filters, as ion storage devices, as ion trap mass analyzers and as ion/ion or ion/molecule reaction cells. In a common configuration, a quadrupole comprises four parallel or substantially parallel rod electrodes that define a central axis and to which a Radio Frequency (RF) oscillatory voltage waveform is applied, with a first RF phase, ϕ, applied to a first set of diametrically opposed rods and a second RF phase, equal to (ϕ+π) applied to the other pair of diametrically opposed rods.
During operation in “RF-only” mode, ion species comprising a wide range of mass-to-charge ratio (m/z) values assume so-called “stable” trajectories between the rods and thus remain confined within the quadrupole to a zone about the central axis. If electrical potential barriers are imposed via gate electrodes at either end of such an RF-only quadrupole, then it may function as an ion store. However, if an electrical potential gradient is applied between the two ends, then the apparatus is an ion guide.
If an additional direct-current (DC) potential difference is applied between the two pairs of diametrically opposed rods (that is, with the rods of one pair at a first potential and the rods of the other pair at a second potential), then a quadrupole may be operated as a mass filter. The difference between the DC potential applied to the first pair of rods and the second pair of rods is herein referred to as a “resolving DC voltage”. The motion of ions in such a device is subject to the well-known Mathieu equation, the various parameterized solutions of which are as shown in a conventional Mathieu stability diagram, as depicted in FIG. 8A. An ion of a specific mass-to-charge ratio (m/z) will have a stable trajectory within the quadrupole if the applied RF and DC voltage amplitudes, respectively V and U, the RF frequency, Ψ, the dimensional parameter, r0, and the ion's m/z are all such that the Mathieu q and a parameters plot within the “X & Y” stable region of the diagram. Such stable-trajectory ions can pass through the quadrupole whereas other ions whose m/z values correspond to either the “Y Unstable” or the “X Unstable” region will ejected off axis and/or neutralized.
The hypothetical ion species that corresponds to point 15 in FIG. 8B is an example of an ion species that would have a stable trajectory within a quadrupole and that would accordingly be able to pass completely through the quadrupole. Given a sample of ions comprising numerous species having respective different m/z values, all such ions correspond to points along line 11, the extension of which passes through the origin of the plot. Thus, all ion species whose Mathieu a and q points plot along the solid-line portion of line 11 that is disposed between intersection points 12 and 14 can pass through the quadrupole. Conversely, hypothetical ion species of the sample whose Mathieu a and q points plot along the dashed-line portions of line 11, such as points 13 and 16, would not pass completely through the quadrupole. The range of m/z values corresponding to all points within the solid-line portion of line 11 may be referred to as the bandpass of the quadrupole mass filter. Generally, when isolating ion species, it is desirable to choose the bandpass to be as narrow as possible, which may be accomplished by increasing the U/V ratio so that the line 11 passes closely to the apex 18 of the diagram.
Qualitative and quantitative mass spectral studies are frequently performed using one or more quadrupoles operating as mass filters. In the experimental mode of operation known as selected ion monitoring (SIM) or multiple ion monitoring (MIM), individual discrete selected ion species of interest are transmitted to a detector, one at a time and without fragmentation. This mode of operation is useful when only certain specific pre-determined analyte compounds are being searched for or otherwise targeted and the initial ionization of each such compound yields at least one diagnostic ion species (i.e., a respective diagnostic m/z value per compound). In an ideal case, only ions comprising a single one of the pre-determined m/z values can pass through the quadrupole to a detector at each detection step, with ions of all other m/z values being filtered out. In general practice, the analysis is performed using a narrow bandpass (e.g., ±1 Th) at each filtering step.
Other common experimental studies employ multi-stage or tandem mass spectrometry that includes two or more stages of mass selection, separation and/or analysis, typically with ions being fragmented between these stages. For instance, a tandem quadrupole mass spectrometer generally consists of first quadrupole that is operated as a mass filter, followed by a second quadrupole that is operated as a collision cell, followed by a third quadrupole that is operated as a mass filter, followed by an ion detector. The procedure for performing tandem mass spectrometry so as to identify a particular analyte is sometimes referred to as selected reaction monitoring (SRM), where the first quadrupole mass filter is initially set to only transmit parent or precursor ions having a single specific pre-determined precursor-ion m/z. These precursor ions are then fragmented in the collision cell and the resulting fragment ions are directed towards the third quadrupole (a second mass filter) which is set to transmit only fragment ions having a specific pre-determined fragment-ion m/z towards the ion detector. Each so-called “reaction” or “transition” of an SRM experiment thus comprises a precursor-fragment ion pair. In targeted experiments, the particular precursor-ion m/z values that are to be isolated for subsequent fragmentation and the particular fragment-ion m/z values that are to be isolated for subsequent detection may be pre-determined prior to an experiment. Alternatively, in so-called data-dependent experiments, the results of immediately preceding measurements may form the basis for automatic real-time software decision steps that determine which specific precursor ion species are fragmented.
When conducting mass spectral studies according to any of the mass spectral modes of operation discussed above, it is necessary to re-configure the operation of at least one quadrupole mass filter so that, after the reconfiguration, it will isolate an ion species having an m/z value that differs from the m/z value an ion species that was previously isolated by the same quadrupole mass filter (in other words, selectively transmitted completely through the quadrupole mass filter). A schematic example of such reconfiguration is illustrated in FIG. 8B. For example, assume that point 15 represents the Mathieu plot of the pre-determined m/z value, (m/z)1, of a first ion species while that species is being isolated. Further assume that that point 13 represents the plot of the pre-determined m/z value, (m/z)2, of the other ion species during the time that the first ion species, (m/z)1, is being isolated. The applied DC voltage, U, and RF voltage amplitude, V, are held constant during the period of time, termed a “dwell time”, that the first ion species is being isolated. Because point 13 is disposed within the “Y Unstable” field of the diagram, the (m/z)2 species is prevented from completely passing through the quadrupole during this dwell time period.
Subsequently, the quadrupole mass filter is rapidly reconfigured so that the (m/z)2 species is able to completely pass through the quadrupole mass filter. The reconfiguration causes the Mathieu representation of (m/z)2 to move from point 13 to point 15 and also causes the Mathieu representation of (m/z)1 to move from point 15 to point 16. In the reconfigured state, the trajectories of the (m/z)2 ion species are stable whereas the those of the (m/z)1 ion species are unstable. In this reconfigured state, the applied DC voltage, U, and applied RF voltage amplitude, V, are held constant at their new values during for a second dwell time period while the second ion species is being isolated. From the diagram, it may be seen that the reconfiguration corresponds to an essentially discontinuous change, Δa, in the Mathieu a parameter as well as a simultaneous essentially discontinuous change, Δq, in the Mathieu q parameter. Operationally, the reconfiguration corresponds to simultaneous essentially discontinuous changes in DC voltage, U, and RF voltage amplitude, V.
Unfortunately, it is found that, when the voltage set-points are rapidly changed from a first setting to a second setting, the electrical system responds with a period of hysteresis comprising multiple voltage overshoots interspersed with undershoots. During the hysteresis period, it is not possible to reliably isolate any particular ion species and further analysis operations must therefore be delayed until the voltages settle at stable constant values. Because of the abrupt drop in the applied voltages, several milliseconds are generally required for the voltages to stabilize. This “settling time” is the extra time needed, before a next measurement or scan can be performed and data collected, for the RF and DC voltages to stabilize and for a resulting stable ion flux to be received at a detector. The inventors have found that the settling time depends on both the difference between the initial and final m/z values as well as on the final m/z value, as discussed further herein below.
Increased speed of resumption of data acquisition after stabilization of quadrupole mass filter voltages is advantageous for applications that target tens or hundreds of SRM transitions. Timely setting of RF/DC voltages on the rods of the quadrupole mass filter after each transition is particularly important to guarantee efficient, reproducible performance at very short dwell times.
U.S. Pat. No. 9,548,193 discloses a mass spectrometer with a quadrupole mass filter for selectively allowing an ion having a specific m/z to pass therethrough, a quadrupole driver for applying a predetermined voltage to each of the electrodes comprising the quadrupole mass filter, and a controller for controlling the quadrupole driver in such a manner as to change the voltage applied to each of the electrodes of the quadrupole mass filter during the scan measurement for a plurality of masses, while changing the waiting time from the termination of one cycle to the initiation of the subsequent cycle in accordance with the mass difference between the initiation mass and the termination mass in a cycle. The step of reducing the mass width of the scan range is said to reduce the time which does not substantially contribute to the mass analysis as much as possible so as to shorten the cycle period. While this approach may reduce the settling time from one cycle to the next, the mass difference between the initiation mass and the termination mass in a cycle can still lead to a larger than ideal voltage overshoot or undershoot, resulting in longer than necessary settling times. Furthermore, the longer settling time needed from cycle to cycle causes undesired ions to remain inside the mass quadrupole filter and reach the detector, which impedes an acquisition of accurate signal intensity.
What are therefore needed are methods of optimizing the operation of a quadrupole mass filter or of a mass spectrometer system comprising one or multiple quadrupole mass filters, such that RF/DC settling times and other delay times that are associated with the quadrupole mass filter or mass filters are accurately accounted for, which will allow measurement of more transitions and acquisition of more data points, per unit of time, without loss of data quality. Preferably, mass spectral data acquisition should not begin prior to voltages becoming stable at the end of a settling period but the commencement of such data acquisition should occur as soon as possible after or, preferably, immediately at the end of the settling period.